The long-term and overall objectives of this research proposal are to gain knowledge on the regulation and mechanisms of hormone action, with particular emphasis on thyroid hormone. The general approach to achieve this goal is to exploit the errors of nature as clues for the elucidation of the normal pathways of hormone action. Data obtained from such research would inevitably provide information on possible therapeutic approaches in inborn defects of hormone action. Measurements of tissue and metabolic responses to the administration of graded doses of thyroid hormone to normal individuals will be compared to those obtained in patients with the syndrome of resistance to thyroid hormone (RTH) in order to establish a comprehensive and rapid method for the diagnosis of this condition. Studies on hormone receptor and a number of cellular responses to thyroid hormone in cultured fibroblasts from patients with RTH will serve to demonstrate the presumed heterogeneous nature of this syndrome. Demonstration of intracellular defects should lead to the identification of steps involved in the normal expression of thyroid hormone action. The incidence of RTH and thus its importance as a casue of morbidity will be determined using data obtained from established neonatal screening programs for hypothyroidism. Uptake, metabolism and metabolic responses to thyroid hormone will be carried out in an established human hepatoma cell line (Hep G2). This system will serve to study serum factors which presumably alter the cellular transfer and action of the hormone in some patients with non-thyroidal illnesses. Two genetic variants of thyroxine-binding globulin (TBG), namely that encountered in Australian Aborigines and in some Blacks will be investigated. The molecular structure of these variant TBGs, identified by their altered affinity to thyroid hormone and by their microheterogeneous pattern on isoelectric focusing, will be studied utilizing biochemical, immunologic and recombinant DNA techniques. The pattern of inheritance, in particular X-chromosome linkage, will be determined. The possible genetic origin of the multiple species of common type of circulating TBG will be studied. The evolution of the structure of TBG will be studied in monkeys. Hormones known to affect the serum level of TBG will be studied utilizing the Hep G2 cell line. Their effect on TBG synthesis, secretion and degradation will be determined in order to gain knowledge on their mode of action.